RESUMEN
Expression of the inhibitory receptor programmed death 1 (PD-1) on cytomegalovirus (CMV)-specific CD4 T cells defines a phenotype associated with CMV viremia in transplant recipients. Moreover, CD28(-) CD27(-) double negativity is known as a typical phenotype of CMV-specific CD4 T cells. Therefore, the co-expression of inhibitory receptors on CD28(-) CD27(-) CD4 T cells was assessed as a rapid, stimulation-independent parameter for monitoring CMV complications after transplantation. Ninety-three controls, 67 hemodialysis patients and 81 renal transplant recipients were recruited in a cross-sectional and longitudinal manner. CMV-specific CD4 T cell levels quantified after stimulation were compared to levels of CD28(-) CD27(-) CD4 T cells. PD-1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expression on CD28(-) CD27(-) CD4 T cells were related to viremia. A percentage of ≥0.44% CD28(-) CD27(-) CD4 T cells defined CMV seropositivity (93.3% sensitivity, 97.1% specificity), and their frequencies correlated strongly with CMV-specific CD4 T cell levels after stimulation (r = 0.73, p < 0.0001). Highest PD-1 expression levels on CD28(-) CD27(-) CD4 T cells were observed in patients with primary CMV viremia and reactivation (p < 0.0001), whereas CTLA-4 expression was only elevated during primary CMV viremia (p < 0.05). Longitudinal analysis showed a significant increase in PD-1 expression in relation to viremia (p < 0.001), whereas changes in nonviremic patients were nonsignificant. In conclusion, increased PD-1 expression on CD28(-) CD27(-) CD4 T cells correlates with CMV viremia in transplant recipients and may serve as a specific, stimulation-independent parameter to guide duration of antiviral therapy.
Asunto(s)
Antígenos CD28/metabolismo , Linfocitos T CD4-Positivos/citología , Infecciones por Citomegalovirus/complicaciones , Receptor de Muerte Celular Programada 1/metabolismo , Insuficiencia Renal/sangre , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Viremia/complicaciones , Adulto , Antivirales/química , Estudios de Casos y Controles , Estudios Transversales , Citomegalovirus , Citometría de Flujo , Humanos , Trasplante de Riñón , Persona de Mediana Edad , Fenotipo , Complicaciones Posoperatorias , Diálisis Renal , Insuficiencia Renal/complicaciones , Insuficiencia Renal/terapia , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: DNA sequencing is the gold standard for hepatitis B virus (HBV) genotyping. We investigated the intergenotypic discriminatory capabilities of various target gene regions over the entire HBV genome, introducing a novel data evaluation approach generally applicable in viral genotyping. METHODS: Complete genome sequences of seventy HBV variants obtained from the sera of 50 Syrian patients were determined and assigned GenBank accession No. from JN257148 to JN257217. Nucleotide sequence contigs were analyzed together with the NCBI reference genome set of HBV genotypes. Nine target gene regions were analyzed by phylogenetic and scored BLAST analyses. Thirty-one overlapping 300-bp sequence segments over the entire genome were also analyzed using a scored BLAST analysis, and intergenotypic discriminatory capabilities were statistically estimated for each. RESULTS: Intergenotype discrimination was extremely significant when targeting either the complete genome, the entire coding sequence of either P or S genes, or any 300-bp sequence segment over the coding sequences of S protein or the polymerase N-terminal domain. Interestingly, intergenotypic discriminatory capability correlated negatively with intragenotype variation. CONCLUSIONS: The intragenotypic conservation of certain target gene regions determines the intergenotypic discriminatory capability and allows reliable genotyping with relatively short segments. Our referential genome-wide tabulated guide allows for selecting candidate target gene regions for sequencing-based HBV genotyping. © 2013 S. Karger AG, Basel.
Asunto(s)
Virus de la Hepatitis B/clasificación , Virus de la Hepatitis B/genética , Tipificación Molecular/métodos , Análisis de Secuencia de ADN/métodos , Virología/métodos , Análisis por Conglomerados , ADN Viral/química , ADN Viral/genética , Genoma Viral , Humanos , Datos de Secuencia Molecular , Filogenia , Homología de Secuencia , SiriaRESUMEN
BACKGROUND: There is an urgent need for improved influenza vaccines especially for older adults due to the presence of immunosenescence. It is therefore highly relevant to compare enhanced influenza vaccines with traditional influenza vaccines with respect to their effectiveness. OBJECTIVE: To compare vaccine efficacy and effectiveness of adjuvanted influenza vaccines (aTIV/aQIV) vs. non-adjuvanted standard-dose (TIV/QIV) and high-dose (TIV-HD/QIV-HD) influenza vaccines regarding influenza-related outcomes in older adults, complementing findings from the European Centre for Disease Prevention and Control (ECDC)'s systematic review of enhanced seasonal influenza vaccines from February 2020. METHODS: A systematic literature search was conducted in Embase and MEDLINE to identify randomised controlled trials, observational studies and systematic reviews, published since ECDC's systematic review (between 7 February 2020 and 6 September 2021). Included studies were appraised with either the Cochrane Risk of Bias tool, ROBINS-I or AMSTAR 2. RESULTS: Eleven analyses from nine real-world evidence (RWE) studies comprising â¼53 million participants and assessing the relative vaccine effectiveness (rVE) of aTIV vs. TIV, QIV and/or TIV-HD in adults aged ≥65 years over the 2006/07-2008/09 and 2011/12-2019/20 influenza seasons were identified. Nine analyses found that aTIV was significantly more effective than TIV and QIV in reducing influenza-related outcomes by clinical setting and suspected influenza outbreaks (rVE ranging from 7.5% to 25.6% for aTIV vs. TIV and 7.1% to 36.3% for aTIV vs. QIV). Seven analyses found similar effectiveness of aTIV vs. TIV-HD in reducing influenza-related medical encounters, inpatient stays and hospitalisations/emergency room visits. In three analyses, aTIV was significantly more effective than TIV-HD in reducing influenza-related medical encounters and office visits (rVE ranging from 6.6% to 16.6%). Risk of bias of identified studies was moderate to high. CONCLUSIONS: Our study suggests that both adjuvanted and high-dose vaccines are effective alternatives for vaccination programmes in older adults and preferable over conventional standard-dose vaccines.
Asunto(s)
Vacunas contra la Influenza , Gripe Humana , Adyuvantes Inmunológicos , Anciano , Humanos , Gripe Humana/prevención & control , Polisorbatos , EscualenoRESUMEN
Cytomegalovirus (CMV) represents a major cause of infectious complications after transplantation. Recently, chronic infections with lymphocyte choriomeningitis virus (LCMV), HIV or HCV were shown to be associated with functionally exhausted T cells characterized by high expression of the programmed death (PD)-1 molecule and altered cytokine expression patterns. We therefore hypothesized that functional exhaustion of CMV-specific CD4 T cells may determine impaired CMV control in patients after renal transplantation. In viremic transplant recipients, a significantly higher proportion of CMV-specific CD4 T cells was PD-1 positive (median 40.9%, 17.0-88.7%) as compared to nonviremic transplant patients (8.8%, 0.8-80.5%), dialysis patients (8.8%, 0-36.7%) or controls (3.2%, 0.3-15.4%, p < 0.0001). In line with functional impairment, PD-1-positive T cells produced significantly less IFNgamma as compared to PD-1-negative T cells (p < 0.0001). Moreover, unlike controls or nonviremic patients, CMV-specific T cells from viremic patients showed a significant loss of IL-2 production (p < 0.0001). Interestingly, functional anergy of CMV-specific CD4 T cells was reversible in that antibody-mediated blockade of PD-1 signaling with its ligands PD-L1/-L2 led to an up to 10-fold increase in CMV-specific proliferation. In conclusion, expression of PD-1 defines a reversible defect of CMV-specific CD4 T cells that is associated with viremia, and blocking PD-1 signaling may provide a potential target for enhancing the function of exhausted T cells in chronic CMV infection.
Asunto(s)
Antígenos CD/biosíntesis , Proteínas Reguladoras de la Apoptosis/biosíntesis , Linfocitos T CD4-Positivos/metabolismo , Infecciones por Citomegalovirus/metabolismo , Interleucina-2/biosíntesis , Trasplante de Riñón , Adulto , Anciano , Linfocitos T CD4-Positivos/virología , Estudios de Casos y Controles , Anergia Clonal , Citomegalovirus/metabolismo , Infecciones por Citomegalovirus/virología , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1 , Carga Viral , Viremia/metabolismo , Replicación ViralAsunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antivirales/uso terapéutico , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Trasplante de Hígado , Trastornos Linfoproliferativos/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/patología , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoterapia , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/virología , RituximabRESUMEN
A commercial line blot using recombinant antigens was compared with a commercial ELISA and 'in-house' IFA (reference test). Two panels were evaluated: Panel A was selected to distinguish between primary infections (89), past infections (20) and seronegatives (8) in immunocompetent individuals. In panel B, patients with a high number of reactivations were included: immunosuppressed patients (37), lymphoma (19), nasopharyngeal carcinoma (10), chronic fatigue syndrome (14). Blood donors (43) and cross-reactive sera (29) were added as controls. Line blot and IFA were concordant in 94% of primary infections, 100% of seronegatives and 100% of past infections, similar to ELISA. Results differed significantly with regard to reactivations. When compared with IFA, the incidence of reactivations was overestimated by the blot, 24 and 58% in blood donors and cross-reactive sera, respectively. ELISA showed a similar problems with 21 and 34% indeterminate results, respectively. The line blot is easy to carry out, has a good concordance with the reference IFA for primary infections, and is, therefore, a sufficient choice for distinguishing primary infection from seronegative and past infection. EBV reactivation assessment will require other methods such as EBV viral load.
Asunto(s)
Anticuerpos Antivirales/sangre , Infecciones por Virus de Epstein-Barr/sangre , Herpesvirus Humano 4/inmunología , Enfermedad Aguda , Carcinoma/sangre , Síndrome de Fatiga Crónica/sangre , Humanos , Immunoblotting/métodos , Huésped Inmunocomprometido , Mononucleosis Infecciosa/sangre , Linfoma/sangre , Neoplasias Nasofaríngeas/sangre , Pruebas SerológicasRESUMEN
BACKGROUND: Alpha1-antitrypsin (α1AT) deficiency caused by Z allele homozygosity represents a well-established risk factor for hepatocellular carcinoma. Previous studies have also implicated α1AT Z heterozygosity in cholangiocarcinogenesis. AIM: To assess the 'common' Z and S alleles as well as the promoter variant rs8004738 for association with cholangiocarcinoma. METHODS: We genotyped 182 Caucasian patients and 350 controls for rs28929474 (Z), rs17580 (S) and the variant rs8004738. Exploratory analyses were performed in relation to gender and cholangiocarcinoma localisation. RESULTS: rs28929474 was significantly enriched in the cholangiocarcinoma group (4.1 vs. 1.7%; OR 2.46, 95% CI 1.14-5.32; Bonferroni corrected p(c) = 0.036), reinforced by Armitage trend testing (OR 2.53; p(c) = 0.032). The rs8004738 (promoter) minor allele tended to be overrepresented in Z heterozygotes (30.0 vs. 16.7%: P = 0.13). Exploratory data analyses suggested a high genetic risk for extrahepatic tumour localisation (OR 3.0; p(c) = 0.016) and potentially female Z allele carriers (OR 3.37; unadjusted P = 0.022, p(c) = 0.088). CONCLUSIONS: These data point to a novel role of α1AT Z heterozygosity as a potential genetic susceptibility factor for cholangiocarcinoma formation and suggest a contribution of aberrant α1AT function in biliary carcinogenesis. However, given the overall low rs28929474 minor allele frequency, larger studies are warranted to confirm and extend our findings.
Asunto(s)
Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos , Colangiocarcinoma/genética , alfa 1-Antitripsina/genética , Anciano , Alelos , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Población Blanca/genéticaRESUMEN
A survey-based, cost-benefit analysis was performed comparing blood screening strategies with vaccination strategies for the reduction of transfusion transmission of HBV. 231 whole blood donors and 126 apheresis donors were eligible and completed a questionnaire detailing their donation habits. The cost-benefit analysis included current mandatory HBV testing (HbsAg+anti-Hbc, A1), A1 with additional nucleic acid testing (NAT) for minipool (A2) or individual donation testing (A3), as well as HBV vaccination strategies using time-dependant (B1) or titre dependent booster vaccination solely (B2), or B2 in addition to current mandatory testing procedures (B3). Different cost models were applied using a 5% rate of discount. Absolute costs for current mandatory testing procedures (A1) over 20 years in Germany were 1009 million. Additional NAT would lead to incremental costs of 43% (A2) or 339% (A3), respectively. Vaccination strategies B1 and B2 showed cost-reductions relative to A1 of 30% and 14%, respectively. The number of remaining HBV infections could be reduced from 360 (for A1) to 13, using vaccination, compared with 144 or 105 remaining infections for A2 or A3, respectively. Absolute cost per prevented infection is similar (2.0 million) for A2 and B3. HBV vaccination offers the near-elimination of transfusion infections while representing a potential cost-reduction.
Asunto(s)
Donantes de Sangre , Hepatitis B/prevención & control , Hepatitis B/transmisión , Reacción a la Transfusión , Vacunación/economía , Adulto , Análisis Costo-Beneficio , ADN Viral/sangre , Selección de Donante/métodos , Femenino , Alemania , Antígenos del Núcleo de la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Humanos , Masculino , Modelos Económicos , Encuestas y CuestionariosRESUMEN
The case report is about an infant suffering from coumarin embryopathy and coumarin syndrome after its mother underwent phenprocoumon treatment (Marcumar, Falithrom) during pregnancy (until 26th week of gestation). Interestingly, a hearing disorder was diagnosed, which had never been described in context with this substance. The coumarin derivatives warfarin, acenocoumarol and phenoprocoumon were compared with regards to spontaneous abortion rate, perinatal mortality and teratogenic risk. Eye anomalies or malformations seem to appear only under warfarin treatment, whereas CNS-malformations are more frequent under phenprocoumon. As a consequence, phenprocoumon treatment of fertile women seems rather doubtful. Upon discovery of a pregnancy under coumarin treatment, vitamin K should immediately be substituted in order to minimize the risk of anomalies and malformation.
Asunto(s)
Anomalías Inducidas por Medicamentos/etiología , Cumarinas/efectos adversos , Enfermedades de las Válvulas Cardíacas/tratamiento farmacológico , Embolia y Trombosis Intracraneal/tratamiento farmacológico , Fenprocumón/efectos adversos , Complicaciones Cardiovasculares del Embarazo/tratamiento farmacológico , Anomalías Múltiples/inducido químicamente , Adulto , Cumarinas/administración & dosificación , Femenino , Humanos , Recién Nacido , Fenprocumón/administración & dosificación , Embarazo , Factores de RiesgoRESUMEN
BACKGROUND: Patients on renal replacement therapy, haemodialysis (HD), or after kidney transplantation (TX), are known to be at risk of acquiring blood-borne infections (HBV, HCV). GBV-C/Hepatitis G virus (HGV) has been described recently and is considered to cause blood-borne infections. The aim of this study was to analyse the risk for the medical staff of HD and TX patients to acquire HGV infection. METHODS: Eighty-five HD patients and 86 TX recipients were compared with 49 health-care workers and 64 blood donors as controls. The HGV prevalence was determined by RT-PCR and antibodies to E2 protein. RESULTS: A high prevalence of HGV was found in the medical staff (24%) which nearly corresponded to the prevalence of the patients (TX 36%, HD 25%) but not to the controls (9%). In contrast, the prevalence of HCV was low in the medical staff (2%) and controls (0%) but high in HD (13%) and TX (13%). Age and duration of employment in the department did not significantly influence the HGV prevalence in staff. The number of viraemic subjects in staff was high, possibly indicating a more recent infection. CONCLUSION: An occupational risk for HGV exists in medical staff of dialysis and transplant patients. Further routes of transmission than only parenteral may play a role in this setting.